Lipid droplets: platforms with multiple functions in cancer hallmarks

Abstract

Lipid droplets (also known as lipid bodies) are lipid-rich, cytoplasmic organelles that play important roles in cell signaling, lipid metabolism, membrane trafficking, and the production of inflammatory mediators. Lipid droplet biogenesis is a regulated process, and accumulation of these organelles within leukocytes, epithelial cells, hepatocytes, and other nonadipocyte cells is a frequently observed phenotype in several physiologic or pathogenic situations and is thoroughly described during inflammatory conditions. Moreover, in recent years, several studies have described an increase in intracellular lipid accumulation in different neoplastic processes, although it is not clear whether lipid droplet accumulation is directly involved in the establishment of these different types of malignancies. This review discusses current evidence related to the biogenesis, composition and functions of lipid droplets related to the hallmarks of cancer: inflammation, cell metabolism, increased proliferation, escape from cell death, and hypoxia. Moreover, the potential of lipid droplets as markers of disease and targets for novel anti-inflammatory and antineoplastic therapies will be discussed.

Fig. 1. Lipid droplets as players in hallmarks of cancer.

Based on the increasingly information about the role of lipid droplets in cancer, emerging from several different models, we suggest the association of lipid droplets with some of the currently established Hallmarks of Cancer—biological traits acquired by cells during cancer multistep development, a concept originally conceived by Hanahan and Weinberg in 2000. Although there are many unanswered questions of fundamental importance to better understand the relationship between these organelles and tumorigenesis, these associations may be explored for future anticancer therapies.

Fig. 2. Mechanisms of lipid droplet biogenesis in cancer.

Different stimuli and cellular pathways contribute for lipid droplets formation, depending on environmental conditions, such as hypoxia, obesity, infection, or extracellular signaling molecules. These processes invariably involve changes in gene expression that regulates de novo lipid synthesis, induction of extracellular lipid uptake and LD biogenesis. Lipid droplets formed by these different stimuli harbor specific lipid content; and a set of enzymes directly related to lipogenesis, such as FAS and DGAT, promote its increase. Lipolytic enzymes could also be located in lipid droplets for fatty acid mobilization upon activation. ABHD5 α-β hydrolase domain containing 5 (also known as CGI-58—Comparative Gene Identification-58), ACC acetyl-CoA carboxylase, ATGL adipose triglyceride lipase, DGAT diacylglycerol O-acyltransferase, DAG diacylglycerol, FA fatty acid, FABP fatty acid-binding protein, FAS fatty acid synthase, G0S2 G0/G1 switch 2, HIF hypoxia-inducible factors, mTOR mammalian target of rapamycin, PI3K phosphoinositide 3-kinase, PLIN2 perilipin-2, PPARγ peroxisome proliferator-activated receptor gamma, RXR retinoid X receptor, SatFA saturated fatty acid, SCD stearoyl-CoA desaturase, SREBP sterol regulatory element-binding protein, TAG triacylglycerol, TLR4 Toll-like receptor, TRIF TIR-domain-containing adapter-inducing interferon-β, UnsatFA unsaturated fatty acids, CD36 fatty acid translocase, CE cholesteryl ester, FC free cholesterol, LDL low-density lipoprotein, LDL-R low-density lipoprotein receptor, SRB1 scavenger receptor class B type, ACAT acyl-CoA:cholesterol acyltransferase.

Fig. 3. Lipid droplets roles in tumor microenvironment.

Lipid droplets (LDs) were associated with distinct roles in heterogeneous cell population of tumor microenvironment. In tumor cells, LDs are sites of PGE₂ (prostaglandin E₂) synthesis, an important immune suppressive eicosanoid, and are associated with proliferation and activation of cancer stemness pathways. Adipocytes release cytokines and fatty acids to fuel metastasis and aggressiveness. In myeloids derived cells, LDs were associated with polarization of TAM (tumor-associated macrophage), a modulatory phenotype of MDSCs (myeloid-derived suppressor cells) and in dendritic cell, LDs enriched with oxidized triacylglycerol species were associated with antigen presentation dysfunction. ROS reactive oxygen species, MHCI major histocompatibility complex class I protein, COX-2 cyclooxygenase-2, cPLA₂ cytosolic phospholipase A2, AA arachidonic acid, FA fatty acid, CD36 fatty acid translocase.